1. Field of the Invention
The present invention relates to novel polymorphic and pseudopolymorphic forms of Trandolaprilat, and mixtures thereof, novel methods for producing Trandolaprilat, pharmaceutically acceptable salts of Trandolaprilat, and polymorphic and pseudopolymorphic forms of Trandolaprilat, pharmaceutical compositions including one or more novel Trandolaprilat compounds and methods for treating high blood pressure and/or cardiac insufficiency using one or more novel Trandolaprilat compounds.
2. Background and Related Art
Trandolaprilat {(2S,3aR,7aS)-1-[[(2S)-2-[[(1S)-1-carboxy-3-phenylpropyl]amino]-propanoyl]octahydro-1H-indole-2-carboxylic acid} is an active metabolite of Trandolapril. Trandolapril and Trandolaprilat have the chemical structures that are shown below, respectively, and are both inhibitors of an enzyme known as the Angiotensin Converting Enzyme (“ACE enzyme”). The ACE enzyme is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to angiotensin II, which is a potent peripheral vasoconstrictor that also stimulates secretion of aldosterone by the adrenal cortex and provides negative feedback for renin secretion.
As ACE inhibitors, Trandolapril and Trandolaprilat inhibit ACE activity, which results in an antihypertensive effect. Thus, Trandolapril and Trandolaprilat may be used to lower high blood pressure and to treat cardiac insufficiency and other medical conditions relating to hypertension. Their effect in hypertension appears to result primarily from the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation, decreasing vasoconstriction, decreasing aldosterone secretion and increasing plasma renin.
Trandolapril is the ethyl ester prodrug of Trandolaprilat, which is a nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor. Trandolapril is deesterified to the diacid metabolite, Trandolaprilat. Trandolaprilat is described in the literature as being about eight times more potent than Trandolapril as an inhibitor of ACE activity. While Trandolapril may be administered as oral dosage forms, such as tablets or capsules, there is a transdermal administration using the ACE inhibitor in the form of dicarboxylic acid (e.g. Trandolaprilat), or as a therapeutically active salt, described in published patent application U.S. 2004/0052835 and U.S. Pat. No. 6,303,141.
As is described in published patent application US 2004/0052835, the use of certain non-stabilized ACE inhibitors in a transdermal patch caused problems because of a decomposition of the active ingredients employed in the patch. Such decomposition occurred within a short period of storage time, whereupon the limit for degradation products exceeded the tolerance. It is described in this document that the salts of the active metabolites (=dicarboxylic acids) of ACE inhibitors, which are formed by reaction of the dicarboxylic acids with strong acids (1:1) or bases (1:2), are substantially stable with respect to decomposition.
It is well known that, very disadvantageously, both Trandolapril and Trandolaprilat (unstabilized) have a tendency to decompose in decomposition reactions that occur during their synthesis and/or storage (cyclization to the corresponding diketopiperazine, as is shown below).
Trandolaprilat tends to decompose during its synthesis and isolation, which contaminates the end product and results in loss of yields.
Different methods and ingredients have been developed for the stabilization of Trandolapril and Trandolaprilat, particularly for the formulation of these compounds. See, for example, U.S. Pat. No. 4,743,450 or published patent application number U.S. 2004/0137054.
The aforementioned problems show that there is an ongoing need to develop new, robust and efficient methods for the preparation and stabilization of ACE inhibitors, which tend to decompose. In addition, or alternatively, to the above-described methods, it has been determined that other such methods can include an investigation and evaluation of different crystalline forms of the ACE inhibitors because they can play a decisive role in the stability of the compounds.
In general, a compound can exist in different crystalline forms as well as in a non-crystalline form. Generally a non-crystalline solid is referred to as an “amorphous form,” which consists of disordered arrangements of molecules. Different crystalline forms of the same compound arise from different packing of the molecules in the solid state, which results in different crystal symmetries and/or unit cell parameters. Such crystalline forms are referred to as “polymorphic forms” and/or “non-solvated forms,” which means that they are essentially free of residual organic solvents. If the substances incorporate stoichiometric or non-stoichiometric amounts of water (hydrates), or any other solvent(s) (solvates), in the crystal structure, they are referred to as “pseudopolymorphic forms.”
Many compounds are known to exist in various polymorphic, pseudopolymorphic or amorphous forms. Such different solid forms can have different physical, spectroscopic and/or chemical properties, such as solubilities and dissolution rates, melting points, densities, stabilities and flow properties. For active compounds, solubilities and dissolution rates may have an influence on their bioavailabilities, densities and flow properties, which have to be considered during formulation. Further, chemical and physical (thermodynamical) stabilities of these compounds are important, for example, with regard to decomposition or conversion of thermodynamically less stable (kinetically favored) polymorphs into more stable polymorphs, which can affect the biological activities of these compounds.
Methods for synthesizing Trandolapril are disclosed in, e.g., EP 0084164 (and its counter part U.S. Pat. No. 4,933,361) and in WO 2005/051909.
Methods for suitably preparing Trandolaprilat from Trandolapril are not described in the literature. Although a preparation of a diastereomeric isomer of Trandolaprilat is described in J. Med. Chem. 30, 992-998 (1987), for the isolation of the diacid, it was necessary to lyophilize the mixture produced, and to purify the resulting residue by ion-exchange chromatography on Amberlite IR-120. Disadvantageously, this method is not suitable for a large-scale production of Trandolaprilat.
An additional preparation of Trandolaprilat is described in U.S. Pat. No. 5,101,039. A specific procedure is not provided, and the procedure that is referred to suffers from several disadvantages: it does not provide crystalline material; it requires the removal of water under vacuum; and it relies on the use of di-isopropyl ether as solvent. Crystalline material is clearly more desirable in terms of isolation and purification; removal of water under vacuum is time consuming; and di-isopropyl ether is very prone to forming dangerous peroxides. Thus, this is not a suitable technical process.
In view of the above, it would be beneficial to provide efficient, reliable and robust processes for preparing Trandolaprilat, and salts, polymorphs, pseudopolymorphs and mixtures thereof, on a large scale, and polymorphs and pseudopolymorphs of Trandolaprilat that have an improved stability during synthesis and storage.